The enteric nervous system (ENS) is a complex network of neurons and glia within the bowel wall that controls most aspects of bowel function. Defects in ENS development cause diverse intestinal motility problems including Hirschsprung disease, a problem where the ENS is missing from the end of the bowel. Problems with bowel motility and sensation are also primary characteristics of irritable bowel syndrome. Although Hirschsprung disease is a genetic disorder, new evidence from our laboratory demonstrate that vitamin A deficiency inhibits normal ENS development and predisposes to distal bowel aganglionosis in a mouse model system. We now hypothesize that even mild "subclinical" vitamin A deficiency will increase the risk of Hirschsprung disease in a genetically susceptible infant. If this is correct, then some cases of Hirschsprung disease, and perhaps other intestinal motility disorders, might be prevented by optimizing maternal nutrition. Studies in this proposal will validate this hypothesis in a murine model system, determine which cells depend on vitamin A metabolites for normal ENS development, and test the mechanistic hypothesis that retinoids facilitate ENS precursor migration by reducing Pten accumulation. PUBLIC HEALTH RELEVANCE: Intestinal motility disorders are common, debilitating and difficult to treat. Based on new data we now believe that mild "subclinical" vitamin A deficiency is a risk factor for these disorders including Hirschsprung disease, a problem where the nervous system within the bowel wall (i.e., the enteric nervous system) is completely missing from the end of the bowel. These studies are designed to find new ways to prevent Hirschsprung disease and other intestinal motility disorders.